In-Vitro-In-Vivo Correlation (IVIVC): A Tool In drug Development

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In-Vitro-In-Vivo Correlation (IVIVC) A Tool In
drug Development

• Mr. Somnath Sakore
• Cadila Pharmaceuticals Ltd

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Outline

• Definition of IVIVC
• Purpose of IVIVC
• Levels of IVIVC
• In vitro data
• In vivo data
• IVIVC models
• IVIVC development
• Predictability
• IVIVC in drug development of extended release
  products
• Issues
• Factors to be consider for correlation
  development
• Conclusion

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Definition of IVIVC

• United State Pharmacopoeia (USP) definition of
  IVIVC
• The establishment of a rational relationship
  between a biological property, or a parameter
  derived from a biological property produced by a
  dosage form, and a physicochemical property or
  characteristic of the same dosage Form.
• Food and Drug Administration (FDA) definition of
  IVIVC
• An In-vitro in-vivo correlation (IVIVC) has been
  defined by the Food and Drug Administration
  (FDA) as a predictive mathematical model
  describing the relationship between an in-vitro
  property of a dosage form and an in-vivo
  response.
• e.g., amount of drug absorbed, thus allowing an
  evaluation of the QC specifications, change in
  process, site, formulation and application for a
  biowaiver etc.

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PURPOSE OF IVIVC

• Reduction of regulatory burden
• IVIVC can be used as substitute for additional in
  vivo experiments, under certain conditions.
• Optimization of formulation
• The optimization of formulations may require
  changes in the composition, manufacturing
  process, equipment, and batch sizes. In order to
  prove the validity of a new formulation, which is
  bioequivalent with a target formulation, a
  considerable amount of efforts is required to
  study bioequivalence (BE)
• /bioavailability (BA).

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PURPOSE OF IVIVC

• IVIVC as surrogate for in vivo bioequivalence
  and to support biowaivers (Time and cost saving)
• The main purpose of an IVIVC model to utilize in
  vitro dissolution profiles as a surrogate for in
  vivo bioequivalence and to support biowaivers.
• Scale up post approval changes (Time and cost
  saving during product development)
• validated IVIVC is also serves as justification
  for a biowaivers in filings of a Level 3 (or
  Type II in Europe) variation, either during
  scale-up or post approval, as well as for line
  extensions (e.g., different dosage strengths)
• Less testing in Human

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Levels of IVIVC

• Level A point-point first deconvolution to get
  in vivo drug absorbed, then compare with
  dissolved
• Level B Statistical moments MRT or MDT in vivo
  vs. MDT in vitro
• Level C single point PK parameter vs.
  dissolved

Level B
Level A
Level C
Level A
Malinowski and Marroum, Encyclopedia of Contr.
Drug Deliv.
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FACTORS TO BE CONSIDER IN DEVELOPING A
CORRELATION

• 1. Biopharmaceutics Classification System
  (BCS)
• BCS guidelines are provided by USFDA, WHO, and
  EMEA
• Class I HIGH solubility / High permeability,
• Class II LOW solubility / High permeability,
• Class III HIGH solubility / LOW permeability
• Class IV LOW solubility / LOW permeability
• BCS Criteria
• highly soluble drugs therapeutic dose is
  soluble in 250 mL (pH 1 7.5)
• highly permeable drugs extent of absorption
  gt 90
• (rapidly dissolving no less than 85 within 30
  min,
• USP II / 50 rpm /pH 1 - 6.8 always considered
• similar if 85 released in less than 15 min)

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Biopharmaceutics Classification System
Class Solubility Permeability IVIVC correlation for IR Products
I High High IVIVC correlation if dissolution rate is slower than gastric emptying rate, otherwise limited or no correlation
II Low High IVIVC correlation expected if in in vitro dissolution rate is similar to in vivo dissolution rate , unless dose is very high
III High Low Absorption permeability is rate determining and limited or no IVIV correlation with dissolution rate.
IV Low Low Limited or no IVIV correlation expected.
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Generation of In-Vitro Release Profile

• USP apparatus 1 (basket, 100 rpm) or 2 (paddle,
  5075 rpm)
• Aqueous dissolution medium, 900 ml
• pH 1-1.5, 4-4.5, 6-6.5 7-7.5 at 370C
• A surfactant may be required (For low solubility
  drugs)
• In-vitro food effect
• Rotating dialysis cell method
• Effects of oils, enzymes and pH

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• 2. In vitro dissolution
• Compendial method (justify other method)
• The dissolution profiles of at least 12
  individual dosage units
• from each lot should be determined
• aqueous medium, n 12 (!), CV lt 10
• difference factor f1, similarity factor f2

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• Comparison between dissolution profiles could be
  achieved using a difference factor (f1) and a
  similarity factor (f2)

f1 values up to 15 (0-15)
f2 values greater than 50 (50-100)
n number of time points, Rt dissolution
value of the reference batch at time t, Tt is
the dissolution value of the test batch at time t
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• 3. In vivo absorption (Bioavailability studies)
• Number of subjects 6 to 36.
• Crossover studies are preferred
• formulations with different release rates
• same moiety as measured in vitro
• Washout period of at least five half-lives.
• BA assessed from Plasma or urine data
• AUC, Cmax, Tmax
• In vivo absorption- Wagner-Nelson,
  Loo-Riegelman, and numerical
• convolution methods.

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Generation of In-Vivo Release Profile

• Compartmental Models
• Wagner-Nelson
• Loo-Riegelman
• Linear Systems Models
• Deconvolution
• Convolution
• Mathematically they all yield the same result

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First step Calculation of in vivo release
profiles from plasma concentrations of an oral
solution and different formulations
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Second step Comparison of calculated in vivo
release with in vitro release data for the same
formulations and establishment of a quantitative
correlation model using a linear or non-linear
regression
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IVIVC MODELS
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IVIVC DEVELOPMENT
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IVIVC in the product development process for
extended-release products
J.Emami, J Pharm Pharmaceut Sci
(www.cspscanada.org) 9(2)169-189, 2006
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IVIVC Model Predictability (Validation)
For Cmax
For AUC

• Acceptance criteria According to FDA guidance
• 15 for absolute prediction error (P.E.) of
  each formulation.
• 10 for mean absolute prediction error (P.E.)

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IVIVC Bench Issues (Practical issues)

• Reliable and biorelevant dissolution method and
  apparatus suitability
• Qualification and calibration of equipment, sink
  conditions
• Ability to discriminate non-BE lots
• Apparatus and media for continuous IVIVC (minimum
  3 lots) and tuning with GI conditions
• Accurate deconvolution of the plasma
  concentration-time profile
• e.g., absorbed in-vivo may be reflective of
  processes other than release absorption rate
  limitation is common for CR products
• Dissolution Specifications
• Based on biological findings rather than
  pharmacopeial or mechanistic

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IVIVC Modeling Issues

• Intra- and Inter-subject variation
• High variations can distort the mean data and in
  turn the deconvolution
• Enterohepatic recycling or second peak
• Reproducibility of reference profiles
• Modeling
• Smoothness of input and response functions
• Jumps in input rate functions, e.g., delayed
  release or gastric emptying
• Statistical properties of the models

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Conclusions

• The pharmaceutical industry has been striving to
  find a ways to saving precious resources in
  relevance to the budgets and increasing cost of
  drug development. IVIVC is a tool applied in
  various areas and stages of drug development to
  find a place in the regulatory bodies around the
  world.
• Biorelevant and reliable dissolution profiles can
  predict the in-vivo absorption of drugs from CR
  formulations.
• Batches with similar dissolution will be BE and
  dissimilar dissolution will be non-BE
• Several methods exist for estimating in-vivo
  absorption
• Level A (point-to-point) or B (mean dissolution
  times) correlation can be obtained for BCS class
  1 or 2 drugs
• At least 3 lots (desirable, fast and slow) must
  be established with IVIVC and proper reference.

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Conclusions

• IVIVC is useful in SUPAC and biowaivers can
  save substantial costs and
• time when registering product changes
• Both practical and modeling issues must be
  addressed
• need to develop methodologies and standards for
  non-oral delivery systems, to develop more
  meaningful dissolution and permeation methods.  

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• THANKS!!!